Extended Drug-Resistant Salmonella Typhi Complicated by Atypical Fatal Hemophagocytic Lymphohistocytosis: A Case Report

Extended Drug-Resistant Salmonella Typhi Complicated by Atypical Fatal Hemophagocytic Lymphohistocytosis: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Extended Drug-Resistant Salmonella Typhi Complicated by Atypical Fatal Hemophagocytic Lymphohistocytosis: A Case Report Mahnoor Baig, Waqas Siddiqui, Sara Soomro, Rabia Shah, Mariam Rashid, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6085253/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hemophagocytic lympho histiocytosis is a deadly hyperinflammatory clinical response marked by excessive inflammation and tissue damage that can be secondarily triggered by infections, autoimmune and malignancies. Hemophagocytic lymph histiocytosis is usually caused by viruses and rarely by bacterial infections like Salmonella Typhi. The rising incidence of extended drug-resistant Salmonella Typhi in low-income countries like Pakistan can lead to numerous complications but hardly secondary Hemophagocytic lympho histiocytosis. We report the first case of extended drug-resistant Salmonella Typhi whose management was complicated due to Hemophagocytic lymph histiocytosis. INTRODUCTION Salmonella Typhi fever is one of the common tropical fevers with a prevalence of 11–21 million cases worldwide annually. The emergence of the Extended Drug-Resistant (XDR) Salmonella Typhi in the South Asian region, especially Pakistan, has become a significant infectious disease burden. In 2019, 60% of the total typhoid fever cases in Pakistan were diagnosed as XDR Salmonella Typhi [ 1 ]. While XDR Salmonella Typhi usually presents with fever and abdominal symptoms, it has been associated with numerous rare complications that may become life-threatening. Hemophagocytic lymph histiocytosis (HLH) is a fatal and rare hyperinflammatory state characterized by over-activation of macrophages and T lymphocytes. Many viral fevers including dengue and COVID have been related to secondary HLH [ 2 ]. However, it is quite unusual for HLH to be associated with bacterial infections, especially Salmonella Typhi. We would like to report a case report of a young female who was admitted with XDR Salmonella Typhi which was associated with rare life-threatening HLH. CASE REPORT A 23-year-old married female with no prior comorbidities, presented to Emergency Department (ED) with complains of per-vaginal bleeding for 15 days along with fever and loose stools for 10 days. She had vitals of blood pressure of 100/70 mmHg, pulse of 120/min, febrile with temperature of 101F and respiratory rate of 18/min maintaining saturation on room air. On examination, she was pale and dehydrated, with the rest of systemic examination unremarkable. Her initial blood workup was sent, and an ultrasound pelvis was done which showed a missed abortion ( Table 1 ) . She was admitted to Gynecology Services where she had suction and evacuation. On the 2nd day of admission, she had documented high grade fever of 102F for which her cultures were sent, and Internal Medicine was consulted. On examination, she had blood pressures of 110/70mmHg, pulse of 112/min regular and respiratory rate of 20/min. She was transferred to the Internal Medicine services with an impression of typhoid fever and started on Injection Meropenem. Her ultrasound abdomen showed moderate hepatosplenomegaly and repeat ultrasound pelvis reported no retained product of conception (RPOCs). On 4th day of admission, her blood culture reported XDR Salmonella Typhi fever and she was continued on Injection Meropenem. However, she continued spiking high-grade fever with worsening cytopenias. She developed nasal bleed and became hypotensive, so she was shifted to the High Dependency Unit for monitoring. Considering her worsening clinical condition and cytopenias, her HLH workup was sent. The workup showed that her HLH criteria score was positive with a H-score of 204 points representing 88–93% probability of HLH. She was immediately started on Injection Dexamethasone as per her body surface area along with Injection Meropenem. Within 48hours, her fever subsided, and her blood workup had improved cytopenias. By 10th day of admission, she became afebrile for more than 48hrs and was discharged on oral Azithromycin and tapering doses of dexamethasone. She was followed in Outpatient Department after 1 week of discharge and was afebrile along with normal cell counts. Table 1 Patient Investigations during Hospital Course Investigations 1st Day 3rd Day 5th Day 7th Day 10th Day Hb (gm/dL) 7.1 8.6 8.2 7.5 8.7 Total Leukocyte Count (x 10 9 L) 5.4 2.8 2.5 3 3.7 Neutrophils 76% 35.4% 39.2% 41% 53% Lymphocytes 18.8% 63% 54.8% 49.3% 34% Platelet counts (x 10 5 L) 166 139 85 74 117 Creatinine 0.51 mg/dL Bilirubin Total 0.67 mg/dL Bilirubin Direct 0.37 mg/dL Gamma Glutamyl Transferase (GGT) 590 U/L Alanine Aminotransferase (SGPT/ALT) 52 U/L Alkaline Phosphatase (ALP) 470 U/L Ferritin 2238ng/ml Triglycerides 397mg/dL Fibrinogen 360mg/dL DISCUSSION HLH is a clinical syndrome with uncontrolled hyper-inflammatory state that is classified into primary and secondary HLH. While primary HLH is due to genetic defects in the immune system, secondary HLH can be triggered by infections, malignancies and autoimmune diseases [ 3 ]. The incidence of primary HLH is approximately 1.2 per million individuals but the exact incidence of secondary HLH is not known and can be critical in 22–59% of patients [ 4 ]. Detailed literature review reports very few cases of Salmonella Typhi causing HLH with no cases reported due to XDR Salmonella Typhi till date [ 5 ]. HLH can be a challenging diagnosis as it mimics many diseases due to similar clinical and laboratory manifestations with multi-organ involvement. It is diagnosed by the HLH 2004 diagnostic criteria consisting of molecular diagnosis or fulfillment of five out of eight following criteria: fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, low or absent NK cell activity, hyperferritinemia and soluble CD25 > 2400 U/ml [ 6 ]. Our patient had fulfillment of HLH criteria with a high H-score despite appropriate antibiotics. Whilst severe onset secondary HLH cases require early and aggressive immunosuppressive therapy (steroids vs intravenous immunoglobulins), HLH cases caused by bacterial and parasitic infections usually benefit from targeted anti-infectious treatment alone. Addition of immunosuppressants in Salmonella Typhi related HLH cases can be dependent on organ failure and the clinical condition of patients. Non et al and George et al reported improvement of their patients with antibiotics alone [ 7 , 8 ]. Similarly, a detailed literature review by Sánchez-Moreno et al reported that only 2 out of 11 patients with typhoid fever complicated by HLH required immunosuppression with antibiotics for recovery [ 9 ]. Our patient had persistent fever and worsening cytopenias that improved only after addition of high dose dexamethasone probably as XDR Salmonella Typhi can be quite aggressive compared to other Salmonella strains. Due to the rarity of this association, there are no randomized controlled trials for testing potential therapies. However, supportive care and treatment of the inciting infectious trigger are associated with a 60%-70% chance of recovery [ 7 ]. Management for HLH needs to be started quickly so that irreversible organ damage can be halted. The overall prognosis of secondary HLH depends on the etiology with patients having malignancies reporting the worst prognosis [ 5 ]. Salmonella Typhi related HLH usually has a good prognosis overall. CONCLUSION The rising prevalence of XDR Salmonella Typhi can progress to serious complications like HLH in endemic areas like Pakistan. Persistent fever and worsening cytopenias in XDR Salmonella Typhi patients should raise suspicion of HLH so that appropriate management can be started early. Declarations Funding Declaration: None Conflict of Interest: None Ethical Approval: Not Required Informed Consent: Taken from Patient Consent for Publication: Taken from Patient References Yousafzai MT, Irfan S, Thobani RS, Kazi AM, Hotwani A, Memon AM, et al. Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016–2019. Clinical Infectious Diseases. 2020;71(Supplement 3):S214-S21. Pradeep C, Karunathilake P, Abeyagunawardena S, Ralapanawa U, Jayalath T. Hemophagocytic lymphohistiocytosis as a rare complication of dengue haemorrhagic fever: a case report. J Med Case Rep. 2023 Jun 1;17(1):224. Shekhar S, Radhakrishnan R, Nagar VS. Secondary Hemophagocytic Lymphohistiocytosis Due to Typhoid Fever. Cureus. 2023 Jul 20;15(7):e42175. Tong QJ, Godbole MM, Biniwale N, Jamshed S. An Elusive Diagnosis: Case Reports of Secondary Hemophagocytic Lymphohistiocytosis and Review of Current Literature. Cureus. 2019 Apr 26;11(4):e4548. Fernandes G, Mhashete P, Patwardhan PP. Hemophagocytic lymphohistiocytosis following enteric fever: A rare autopsy case report. Indian J Pathol Microbiol. 2024 Apr 1;67(2):435-437. Kodan P, Chakrapani M, Shetty M, Pavan R, Bhat P. Hemophagocytic lymphohistiocytosis secondary to infections: a tropical experience! J Postgrad Med. 2015 Apr-Jun;61(2):112-5. Non LR, Patel R, Esmaeeli A, Despotovic V. Typhoid Fever Complicated by Hemophagocytic Lymphohistiocytosis and Rhabdomyolysis. Am J Trop Med Hyg. 2015 Nov;93(5):1068-9. doi: 10.4269/ajtmh.15-0385. Epub 2015 Aug 31. PMID: 26324725; PMCID: PMC4703258. George N, Sethi P, Nischal N, Kumar A, Siripurapu G, Wig N, et al. A Catastrophic Presentation of Enteric Fever with Secondary Hemophagocytic Lymphohistiocytosis. J Assoc Physicians India. 2018 Dec;66(12):11-12. Sánchez-Moreno P, Olbrich P, Falcón-Neyra L, Lucena JM, Aznar J, Neth O. Typhoid fever causing haemophagocytic lymphohistiocytosis in a non-endemic country - first case report and review of the current literature. Enferm Infecc Microbiol Clin (Engl Ed). 2019 Feb;37(2):112-116. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6085253","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":421945599,"identity":"b3caa8e0-fd50-4435-8697-fca272706bff","order_by":0,"name":"Mahnoor Baig","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYFACHjCZwMAM4cqBiAMPSNFiDNaSQJQWKEhsQOFiAbrtZ489+FBxL4+/nf3ixx8129Lnhx1+CLTFTk63AbsWszN56YYzzhQXSxzmKZaQOHY7d+PtNAOglmRjswM4tBzIMZPmbUtIbDjMkyBhwAbUMjsBpOVA4jZcWs6/gWiZf5gn+UfCv9vphrPTP+DXcgNqy4bD7MckDrbdTpCXziFgy403ZpIzziQUGx7mYbNs7LttuEE6p+BAggEev5zPMZP4UJGQJ3f++OObP77dlpefnb75w4cKOzlcWpAAjwGYMgCrNCCoHATYH4Ap+QaiVI+CUTAKRsEIAgC8VGgqPN+LbQAAAABJRU5ErkJggg==","orcid":"","institution":"Indus Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mahnoor","middleName":"","lastName":"Baig","suffix":""},{"id":421945601,"identity":"040330d8-4733-4029-bbf1-96700e76f8eb","order_by":1,"name":"Waqas Siddiqui","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Waqas","middleName":"","lastName":"Siddiqui","suffix":""},{"id":421945603,"identity":"06e2ffbb-691a-4655-919e-a6f7652d9e94","order_by":2,"name":"Sara Soomro","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Soomro","suffix":""},{"id":421945604,"identity":"3551f038-6413-45ac-ac46-d6a3c7c0ffc9","order_by":3,"name":"Rabia Shah","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rabia","middleName":"","lastName":"Shah","suffix":""},{"id":421945607,"identity":"d6b17b5a-3f22-4cbf-94e9-9a3a4aef908f","order_by":4,"name":"Mariam Rashid","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mariam","middleName":"","lastName":"Rashid","suffix":""},{"id":421945610,"identity":"0378a66c-f754-4c15-968f-a5b68d5dfb18","order_by":5,"name":"Lubna Abbasi","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lubna","middleName":"","lastName":"Abbasi","suffix":""},{"id":421945611,"identity":"82d88ed8-533c-422b-bd02-8b1868301231","order_by":6,"name":"Muneer Sadiq","email":"","orcid":"","institution":"Indus Hospital","correspondingAuthor":false,"prefix":"","firstName":"Muneer","middleName":"","lastName":"Sadiq","suffix":""}],"badges":[],"createdAt":"2025-02-22 11:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6085253/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6085253/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77639813,"identity":"8b836aaf-e83e-46c6-bac2-d129c5b52398","added_by":"auto","created_at":"2025-03-03 20:16:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":314898,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6085253/v1/23e9cd36-02ae-4e76-82fe-4ed76a88d119.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Extended Drug-Resistant Salmonella Typhi Complicated by Atypical Fatal Hemophagocytic Lymphohistocytosis: A Case Report","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSalmonella Typhi fever is one of the common tropical fevers with a prevalence of 11\u0026ndash;21\u0026nbsp;million cases worldwide annually. The emergence of the Extended Drug-Resistant (XDR) Salmonella Typhi in the South Asian region, especially Pakistan, has become a significant infectious disease burden. In 2019, 60% of the total typhoid fever cases in Pakistan were diagnosed as XDR Salmonella Typhi [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While XDR Salmonella Typhi usually presents with fever and abdominal symptoms, it has been associated with numerous rare complications that may become life-threatening.\u003c/p\u003e \u003cp\u003eHemophagocytic lymph histiocytosis (HLH) is a fatal and rare hyperinflammatory state characterized by over-activation of macrophages and T lymphocytes. Many viral fevers including dengue and COVID have been related to secondary HLH [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, it is quite unusual for HLH to be associated with bacterial infections, especially Salmonella Typhi. We would like to report a case report of a young female who was admitted with XDR Salmonella Typhi which was associated with rare life-threatening HLH.\u003c/p\u003e"},{"header":"CASE REPORT","content":"\u003cp\u003eA 23-year-old married female with no prior comorbidities, presented to Emergency Department (ED) with complains of per-vaginal bleeding for 15 days along with fever and loose stools for 10 days. She had vitals of blood pressure of 100/70 mmHg, pulse of 120/min, febrile with temperature of 101F and respiratory rate of 18/min maintaining saturation on room air. On examination, she was pale and dehydrated, with the rest of systemic examination unremarkable. Her initial blood workup was sent, and an ultrasound pelvis was done which showed a missed abortion \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. She was admitted to Gynecology Services where she had suction and evacuation.\u003c/p\u003e \u003cp\u003eOn the 2nd day of admission, she had documented high grade fever of 102F for which her cultures were sent, and Internal Medicine was consulted. On examination, she had blood pressures of 110/70mmHg, pulse of 112/min regular and respiratory rate of 20/min. She was transferred to the Internal Medicine services with an impression of typhoid fever and started on Injection Meropenem. Her ultrasound abdomen showed moderate hepatosplenomegaly and repeat ultrasound pelvis reported no retained product of conception (RPOCs). On 4th day of admission, her blood culture reported XDR Salmonella Typhi fever and she was continued on Injection Meropenem. However, she continued spiking high-grade fever with worsening cytopenias. She developed nasal bleed and became hypotensive, so she was shifted to the High Dependency Unit for monitoring.\u003c/p\u003e \u003cp\u003eConsidering her worsening clinical condition and cytopenias, her HLH workup was sent. The workup showed that her HLH criteria score was positive with a H-score of 204 points representing 88\u0026ndash;93% probability of HLH. She was immediately started on Injection Dexamethasone as per her body surface area along with Injection Meropenem. Within 48hours, her fever subsided, and her blood workup had improved cytopenias. By 10th day of admission, she became afebrile for more than 48hrs and was discharged on oral Azithromycin and tapering doses of dexamethasone. She was followed in Outpatient Department after 1 week of discharge and was afebrile along with normal cell counts.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Investigations during Hospital Course\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1st Day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3rd Day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5th Day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7th Day\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10th Day\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb (gm/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Leukocyte Count (x 10\u003csup\u003e9\u003c/sup\u003e L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet counts\u003c/p\u003e \u003cp\u003e(x 10\u003csup\u003e5\u003c/sup\u003e L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.51 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilirubin Total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilirubin Direct\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.37 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGamma Glutamyl Transferase (GGT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e590 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine Aminotransferase (SGPT/ALT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline Phosphatase (ALP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e470 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2238ng/ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e397mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrinogen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e360mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHLH is a clinical syndrome with uncontrolled hyper-inflammatory state that is classified into primary and secondary HLH. While primary HLH is due to genetic defects in the immune system, secondary HLH can be triggered by infections, malignancies and autoimmune diseases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The incidence of primary HLH is approximately 1.2 per million individuals but the exact incidence of secondary HLH is not known and can be critical in 22\u0026ndash;59% of patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Detailed literature review reports very few cases of Salmonella Typhi causing HLH with no cases reported due to XDR Salmonella Typhi till date [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHLH can be a challenging diagnosis as it mimics many diseases due to similar clinical and laboratory manifestations with multi-organ involvement. It is diagnosed by the HLH 2004 diagnostic criteria consisting of molecular diagnosis or fulfillment of five out of eight following criteria: fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, low or absent NK cell activity, hyperferritinemia and soluble CD25\u0026thinsp;\u0026gt;\u0026thinsp;2400 U/ml [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our patient had fulfillment of HLH criteria with a high H-score despite appropriate antibiotics.\u003c/p\u003e \u003cp\u003eWhilst severe onset secondary HLH cases require early and aggressive immunosuppressive therapy (steroids vs intravenous immunoglobulins), HLH cases caused by bacterial and parasitic infections usually benefit from targeted anti-infectious treatment alone. Addition of immunosuppressants in Salmonella Typhi related HLH cases can be dependent on organ failure and the clinical condition of patients. Non et al and George et al reported improvement of their patients with antibiotics alone [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Similarly, a detailed literature review by S\u0026aacute;nchez-Moreno et al reported that only 2 out of 11 patients with typhoid fever complicated by HLH required immunosuppression with antibiotics for recovery [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our patient had persistent fever and worsening cytopenias that improved only after addition of high dose dexamethasone probably as XDR Salmonella Typhi can be quite aggressive compared to other Salmonella strains. Due to the rarity of this association, there are no randomized controlled trials for testing potential therapies. However, supportive care and treatment of the inciting infectious trigger are associated with a 60%-70% chance of recovery [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eManagement for HLH needs to be started quickly so that irreversible organ damage can be halted. The overall prognosis of secondary HLH depends on the etiology with patients having malignancies reporting the worst prognosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Salmonella Typhi related HLH usually has a good prognosis overall.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe rising prevalence of XDR Salmonella Typhi can progress to serious complications like HLH in endemic areas like Pakistan. Persistent fever and worsening cytopenias in XDR Salmonella Typhi patients should raise suspicion of HLH so that appropriate management can be started early.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003eFunding Declaration: None\u003c/p\u003e\n\u003cp\u003eConflict of Interest: None\u003c/p\u003e\n\u003cp\u003eEthical Approval: Not Required\u003c/p\u003e\n\u003cp\u003eInformed Consent: Taken from Patient\u003c/p\u003e\n\u003cp\u003eConsent for Publication: Taken from Patient\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYousafzai MT, Irfan S, Thobani RS, Kazi AM, Hotwani A, Memon AM, et al. Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016\u0026ndash;2019. Clinical Infectious Diseases. 2020;71(Supplement 3):S214-S21.\u003c/li\u003e\n\u003cli\u003ePradeep C, Karunathilake P, Abeyagunawardena S, Ralapanawa U, Jayalath T. Hemophagocytic lymphohistiocytosis as a rare complication of dengue haemorrhagic fever: a case report. J Med Case Rep. 2023 Jun 1;17(1):224. \u003c/li\u003e\n\u003cli\u003eShekhar S, Radhakrishnan R, Nagar VS. Secondary Hemophagocytic Lymphohistiocytosis Due to Typhoid Fever. Cureus. 2023 Jul 20;15(7):e42175. \u003c/li\u003e\n\u003cli\u003eTong QJ, Godbole MM, Biniwale N, Jamshed S. An Elusive Diagnosis: Case Reports of Secondary Hemophagocytic Lymphohistiocytosis and Review of Current Literature. Cureus. 2019 Apr 26;11(4):e4548. \u003c/li\u003e\n\u003cli\u003eFernandes G, Mhashete P, Patwardhan PP. Hemophagocytic lymphohistiocytosis following enteric fever: A rare autopsy case report. Indian J Pathol Microbiol. 2024 Apr 1;67(2):435-437. \u003c/li\u003e\n\u003cli\u003eKodan P, Chakrapani M, Shetty M, Pavan R, Bhat P. Hemophagocytic lymphohistiocytosis secondary to infections: a tropical experience! J Postgrad Med. 2015 Apr-Jun;61(2):112-5. \u003c/li\u003e\n\u003cli\u003eNon LR, Patel R, Esmaeeli A, Despotovic V. Typhoid Fever Complicated by Hemophagocytic Lymphohistiocytosis and Rhabdomyolysis. Am J Trop Med Hyg. 2015 Nov;93(5):1068-9. doi: 10.4269/ajtmh.15-0385. Epub 2015 Aug 31. PMID: 26324725; PMCID: PMC4703258.\u003c/li\u003e\n\u003cli\u003eGeorge N, Sethi P, Nischal N, Kumar A, Siripurapu G, Wig N, et al. A Catastrophic Presentation of Enteric Fever with Secondary Hemophagocytic Lymphohistiocytosis. J Assoc Physicians India. 2018 Dec;66(12):11-12. \u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Moreno P, Olbrich P, Falc\u0026oacute;n-Neyra L, Lucena JM, Aznar J, Neth O. Typhoid fever causing haemophagocytic lymphohistiocytosis in a non-endemic country - first case report and review of the current literature. Enferm Infecc Microbiol Clin (Engl Ed). 2019 Feb;37(2):112-116. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6085253/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6085253/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHemophagocytic lympho histiocytosis is a deadly hyperinflammatory clinical response marked by excessive inflammation and tissue damage that can be secondarily triggered by infections, autoimmune and malignancies. Hemophagocytic lymph histiocytosis is usually caused by viruses and rarely by bacterial infections like Salmonella Typhi. The rising incidence of extended drug-resistant Salmonella Typhi in low-income countries like Pakistan can lead to numerous complications but hardly secondary Hemophagocytic lympho histiocytosis. We report the first case of extended drug-resistant Salmonella Typhi whose management was complicated due to Hemophagocytic lymph histiocytosis.\u003c/p\u003e","manuscriptTitle":"Extended Drug-Resistant Salmonella Typhi Complicated by Atypical Fatal Hemophagocytic Lymphohistocytosis: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-03 11:08:14","doi":"10.21203/rs.3.rs-6085253/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2cdc567d-3d19-4973-952c-615f3de493b8","owner":[],"postedDate":"March 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-05T07:08:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-03 11:08:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6085253","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6085253","identity":"rs-6085253","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}